Adaption of neurosurgical resection patterns for pediatric low‐grade glioma spanning two decades—Report from the German LGG‐studies 1996–2018

Abstract Introduction Neurosurgery is considered the mainstay of treatment for pediatric low‐grade glioma (LGG); the extent of resection determines subsequent stratification in current treatment protocols. Yet, surgical radicality must be balanced against the risks of complications that may affect long‐term quality of life. We investigated whether this consideration impacted surgical resection patterns over time for patients of the German LGG studies. Patients and Methods Four thousand two hundred and seventy pediatric patients from three successive LGG studies (median age at diagnosis 7.6 years, neurofibromatosis (NF1) 14.7%) were grouped into 5 consecutive time intervals (TI1‐5) for date of diagnosis and analyzed for timing and extent of first surgery with respect to tumor site, histology, NF1‐status, sex, and age. Results The fraction of radiological LGG diagnoses increased over time (TI1 12.6%; TI5 21.7%), while the extent of the first neurosurgical intervention (3440/4270) showed a reduced fraction of complete/subtotal and an increase of partial resections from TI1 to TI5. Binary logistic regression analysis for the first intervention within the first year following diagnosis confirmed the temporal trends (p < 0.001) and the link with tumor site for each extent of resection (p < 0.001). Higher age is related to more complete resections in the cerebellum and cerebral hemispheres. Conclusions The declining extent of surgical resections over time was unrelated to patient characteristics. It paralleled the evolution of comprehensive treatment algorithms; thus, it may reflect alignment of surgical practice to recommendations in respect to age, tumor site, and NF1‐status integrated as such into current treatment guidelines. Further investigations are needed to understand how planning, performance, or tumor characteristics impact achieving surgical goals.


| INTRODUCTION
Low-grade glioma (LGG) account for almost half of all brain tumors in children and adolescents. 1They have long been described as slow-growing tumors with heterogeneous biologic behavior but excellent long-term survival.In recent years, molecular genetic diagnostics mapped distinctive mutations to various histologic subgroups, 2 though most current treatment recommendations still comprise all pediatric LGG (pLGG) and few protocols stratify for molecular signatures. 3eurosurgery is considered the mainstay of treatment for pLGG, with a role for diagnosis, reduction of mass effect, and tumor removal. 4Although complete resection emerged as favorable prognostic factor, [5][6][7][8] the risks of extended surgical resection for associated neurologic damage were acknowledged and caused debate for the choice of the optimal resection strategy at least for specific tumor sites like the supratentorial midline (SML). 9,10Though key drivers for tumor regrowth or relapse and patterns of behavior of the various tumor subtypes are still not fully understood, size and site of tumor remnants play a significant role 5,11 giving neurosurgeons the challenge to minimize residuals.][14][15][16] Still, the extent of surgical resection represented the pivotal point for subsequent treatment stratification.Following international consensus, 17 tumor resection was even discouraged for intrinsic growth patterns and eloquent sites stressing that surgical radicality needed to be balanced against the risks of complications in order to preserve long-term quality of life.
Successive multicenter studies for pediatric low-grade glioma in Germany had been accompanied by a doubling of annual recruitment over two decades. 1 A concurrent phenomenon was a relative decrease of complete/subtotal tumor removal at first surgery over the successive study periods.][20] Therefore, we analyzed surgical resection patterns in further detail for all patients registered in the HIT-LGG 1996 study, 7 the SIOP-LGG 2004 study, 8 and the LGGregistry. 1 We related the extent of primary resection over time to anatomical location, age at initial surgery, sex, NF1-status, and histological diagnosis.We asked if reductions of the initial degree of resection correlated to changes of such epidemiologic characteristics within the study cohorts or other factors and affected radiological outcome.

| Patients
We included all study patients with pediatric LGG from the population-based German cooperative multicenter Results: The fraction of radiological LGG diagnoses increased over time (TI1 12.6%; TI5 21.7%), while the extent of the first neurosurgical intervention (3440/4270) showed a reduced fraction of complete/subtotal and an increase of partial resections from TI1 to TI5.Binary logistic regression analysis for the first intervention within the first year following diagnosis confirmed the temporal trends (p < 0.001) and the link with tumor site for each extent of resection (p < 0.001).Higher age is related to more complete resections in the cerebellum and cerebral hemispheres.

Conclusions:
The declining extent of surgical resections over time was unrelated to patient characteristics.It paralleled the evolution of comprehensive treatment algorithms; thus, it may reflect alignment of surgical practice to recommendations in respect to age, tumor site, and NF1-status integrated as such into current treatment guidelines.Further investigations are needed to understand how planning, performance, or tumor characteristics impact achieving surgical goals.

K E Y W O R D S
child, extent of resection, low-grade glioma, neurosurgery, treatment algorithm studies HIT-LGG 1996, SIOP-LGG 2004 (Clini calTr ials.gov NCT00276640, EudraCT number 2005-005377-29), and LGG-registry.Inclusion criteria comprised LGG of all CNS localizations in patients aged <18 years (<16 years prior amendment of April 27, 2007), histologic diagnosis of LGG according to the respective World Health Organization (WHO) classification, and no prior treatment.Central review for neuropathology and neuroradiology was recommended.Follow-up included information up to August 4, 2020.
The registration period was segmented into five time intervals (TI) with comparable patient numbers for analysis of the extent of initial surgical resection over time.Time interval 1 (TI1) corresponded to the HIT-LGG 1996 study period (01.10.1996 to 31.03.2004),intervals 2 and 3 (TI2, TI3) matched the first and second half of the SIOP-LGG 2004 study period (01.04.2004 to 31.03.2012), and intervals 4 and 5 (TI4, TI5) the first and second half of the LGG registry period (01.04.2012 to 31.12.2018),respectively.Patients were allocated to these intervals according to the date of their tumor diagnosis, even if their study assignment differed.

| Treatment guidelines
The basic treatment algorithm was identical throughout the entire study period and recommended for all pLGG patients.Following complete resection or incomplete removal without clinically symptomatic or progressive tumor remnants, patients were to be observed.Nonsurgical treatment was indicated for patients with residual tumor and neurological deterioration or continuous tumor progression in whom (re-)resection was deemed unfeasible.Treatment of recurrence or progression was not standardized but included all modalities upon discussion in the local and/or national reference multidisciplinary tumor boards.

| Neurosurgical treatment
All primary tumor-related interventions were included in the analysis, also comprising those beyond adolescence.Despite protocol guidance, neurosurgical interventions cannot be standardized.Thus, decision-making with respect to the extent of resection and timing may have varied during the study period and among participating centers.
The HIT-LGG 1996 protocol recommended "maximal tumor resection or mass reduction" and avoiding risks for post-surgical neurological impairments.Open or stereotactic biopsy should be performed in non-resectable tumors to prove histology of LGG.During the SIOP-LGG 2004 study and LGG registry, "best safe surgical excision" was recommended at diagnosis or relapse, but long-term neurological/ophthalmological risks were emphasized to a greater extent, and disease stability following incompletely resected tumors was accepted as surgical goal.
The extent of the initial tumor-related neurosurgical intervention was rated by the neurosurgeon during and following the intervention and by radiological findings based upon early postoperative scanning within 48-72 h, though categories were primarily defined radiologically as biopsy, partial, subtotal, or complete resection.Extent of resection was complete if there was no evidence of residual tumor, and as subtotal, 21 if a small, non-measurable tumor rim or lining was visible on the postoperative scans.Partial resection was defined by a solid residue in postoperative MR imaging, while (stereotactic, endoscopic, or microsurgical) biopsy left the tumor radiologically unchanged.If biopsy was followed by tumor resection during one hospital stay in a two-staged approach, both interventions were counted as one, and the extent of resection was rated according to the definitive therapeutic surgery.

| Neuroimaging
Central radiologic review for primary tumor location, extent of surgery, and long-term tumor status was performed at the Reference Center for Neuroradiology of the German Society of Pediatric Oncology and Hematology (GPOH), University of Wuerzburg, Germany.Neuro-imaging followed recommendations of the German pediatric brain tumor network ("HIT-Netzwerk") 22 and published consensus by the European SIOP Brain Tumor Imaging Group. 21

| Statistical analysis
For categorical variables, absolute or relative frequencies are given.Continuous variables are described by median and range.The impact of the time interval (TI1-5), age at diagnosis, major tumor site, sex, neurofibromatosis-(NF1-) and tuberous sclerosis complex-(TSC-) status on the pattern of initial surgery was analyzed with multivariable logistic regression.Multivariable model building is described in Data S1.
The German LGG studies had not included predefined neurosurgical questions with respect to the extent of resection.Therefore, all analyses were exploratory, and pvalues were considered as descriptive measures to detect and study meaningful effects.

| Patient cohort
Between October 1st, 1996, and December 31st, 2018, 4317 patients had been registered prospectively into HIT-LGG 1996 (n = 899), SIOP-LGG 2004 (n = 1582), and the LGG registry (n = 1836).Patients with a date of diagnosis prior to 01. 10.1996 (prior to HIT-LGG 1996) were excluded (n = 47); thus, 4270 patients were eligible for analysis and grouped within the five time intervals.Successive cohorts did not differ in their epidemiologic data, which are summarized in Table 1.Patient numbers for the various analyses are detailed in Figure S1.
The extent of the first intervention showed a reduced fraction of complete/subtotal resections from TI1 to TI5, while the fraction of partial resections increased.The fraction of biopsies was similar during all TIs and made up for around 20%. (Figure 2A). of tumors in TI1-4 and in 29.2% in TI5.The fraction of complete removals increased in TI4 for resections delayed beyond day 29.From TI1 to TI5, subtotal resections became infrequent, while the portion of partial resections increased.During all five study intervals, biopsy was performed in 15.3%-19.9% of tumors from day 1 to 28, yet up to 34.1% during later interventions within the first year.The majority of 240 patients with first surgery >1 year had biopsies (40.0%) or partial resections (25.8%), still 29.6% tumors were completely resected (Figure S2A-D and Table S1).
3.2.2| Relation of the interval between diagnosis and first surgery and tumor site (n = 3440) The majority of tumors with resection between days 1 and 28 were located in the cerebellum, the SML, and the cerebral hemispheres.At later time points within the first year, the fraction of hemispheric tumors increased, to a lesser extent for SML sites as well, while interventions for cerebellar LGG made up less than 10% (Figure 1B).SML LGG made up for 52.1% of 240 interventions beyond the first year (Table S2), while 23.3% of those were NF1-associated.
Resection of cerebral hemispheric and cerebellar tumors was mostly complete/subtotal with a declining relative fraction from TI1 (73.5% and 89.5%) to TI5 (48.0% and 58.3%), but an intermittent rise for hemispheric LGG in TI4.In return, the relative fraction of partially resected LGG increased, while biopsy concerned a largely constant, small portion.At all times, temporal LGG were resected less completely compared to the other cerebral regions.
The LGG in infants was diagnosed radiologically in more than a quarter (26.1%) but less often in older patients (≥16 years: 10.6%).If operated, infant LGGs were less often resected completely (11.4% vs. 42.9% in patients ≥16 years), while they were biopsied more often (30.8% vs. 13.2%-16.6% in the other age groups), with no major differences for subtotal and partial resections.
For resections within the first year following diagnosis, the fraction of complete/subtotal resections declined with an increase of partial resections in all age groups over time (Figure 3B-F and Table S4A-E).It is acknowledged that during the 22-year registration period, the histologic classification of LGGs was subject to multiple revisions including the definition of new entities. 23ilocytic astrocytoma (PA) remained the largest group of diagnoses during all time intervals (TI1: 77.5%; TI5: 62.8%).Most PA were resected completely, the fraction of subtotal resections declined and rose for partial resections (18.7% to 42.2%, respectively).Biopsies were performed in 12.5%-19.8%.
The umbrella term of "other LGG" included SEGA, pleomorphic xanthoastrocytoma WHO grade II, and LGG without further specification.Their fraction grew from 4.4% to 10.3%, but subgroups remained too small for further analysis.The extent of resection followed the general trends (Table S5).

| Outcome data
Within the observation time, 158/4270 patients died (3.7%; in median after 3.7 years); a large portion succumbed to progression of their LGG (64/158), though the cause of death had not always been recorded.
At the end of the observation time (median 8.7 years), 38.2% of 4112 surviving patients were in complete remission, 55.3% had stable disease, and 2.3% of tumors were progressive.
Among 666/4270 patients (15.6%) from TI2-5 with incompletely resected tumors and no additional treatment during follow-up, 92 patients attained radiological complete remission, 547 had stable disease, 18 tumors were progressive, and 9 patients had died at the time of the last information (median follow-up 5.9 years).The majority of 914/4270 patients (21.4%) from TI2-5 with complete initial resection and no further treatment remained in complete remission (Figure S4).

| Inferential statistical results
The pattern of the initial surgical procedure over time was analyzed for the first tumor resection status within  the first year after diagnosis.Analyses included all patients with at one surgery (n = 3440) as well as those patients with an observation time of at least 1 year without tumor surgery (791/830) (in total 4231/4270).For these analyses, the resection status of 240/3440 patients with surgery beyond 1 year was censored as not having surgery within the first year, while 39/830 radiologically diagnosed pLGG patients with an observation time of <1 year were excluded from analyses as missing values (n = 6 died, n = 33 without adequate follow-up information, 22/33 in TI5).Time groups differed for median age at diagnosis (lower in TI1) and the fraction of patients within age subgroups, while epidemiologic data were comparable for sex ratio, NF1-status, tumor sites (though growing number of older patients with hemispheric tumors in later time intervals), and dissemination (Table S6).
Binary logistic main effects models (Table 3) revealed steadily declining odds for complete and subtotal resection over time, arriving at an odds ratio of 0.405 and 0.333, respectively, comparing time interval TI5 to TI1.The odds for complete resection were higher in the cerebral hemispheres, the cerebellum, or the spinal cord as compared to the SML or the brainstem.The odds for partial resection rose in the course of time (odds ratio of 2.658 for TI5 vs. TI1) and were notably increased in the brainstem and spinal cord.The odds for biopsy showed no clear change over time.Increasing age at diagnosis only augmented the odds for complete resection.NF1-and TSC-negative patients had higher odds for any extent of resection; sex was non-influential.
A noticeable interaction with the time interval (p ≤ 0.05) was found for the major tumor sites only.For this reason, additional binary logistic regression models were fitted in the subgroups defined by the major tumor sites.This analysis for the major tumor sites (Table S7) confirmed the steady decline of odds for complete and subtotal resection over time in the SML, cerebral hemispheres, and cerebellum.
Age >1 year at diagnosis increased the odds for complete resection in the cerebellum, while only the age groups 10-15 and ≥16 years with their higher portion of hemispheric LGG, especially in the temporal lobe, had higher odds for complete resection the cerebral hemispheres.Over time, the odds for partial resection rose in the hemispheres and cerebellum.In the SML, partial resections were more probable just within the age group 1-4 years at diagnosis.NF1-negative patients had higher odds for any extent of resection in the SML.Sex was noninfluential for any analysis.
The decreasing likelihood over time (from TI1 to TI5) of complete/subtotal versus partial resection/biopsy in the SML, in the cerebral hemispheres, and in the cerebellum was corroborated by multinominal logistic regression analysis.Likewise, higher age at diagnosis increased the probability of complete/subtotal resection of hemispheric and SML LGG, with no impact of the NF1-status at the SML (Table S8).
The decrease of extent of first neurosurgical intervention, however, did not compromise long-term outcome.In fact, 5-year OS improved from 95.9% in TI1 to 98.6% in TI5 (p < 0.001, log-rank test).

| DISCUSSION
Our data document the decrease of the extent of the first neurosurgical intervention without compromising the long-term outcome of pediatric low-grade glioma in Germany between 1996 and 2018, though technical advances that would support neurosurgical resection were introduced at the same time.The odds for having a complete resection at first operation within the first year after diagnosis declined by a factor 2.5 over the recruitment period.Binary logistic regression analysis confirmed the presence of these temporal trends beyond tumor site and age at diagnosis as major influential factors for the probability of a certain extent of resection.For this analysis, we included data on 4270 pLGG patients from three successive prospective and population-based LGG studies with consistent recruitment criteria. 1,7,8We are not aware of a comparable publication analyzing the surgical resection patterns of a large pLGG cohort over more than 2 decades.

| Patient cohort
Epidemiologic data of our cohort have been detailed previously 1 ; they conformed to other international series with the exception of variable age limits for inclusion. 5,6,24][27] Due to the joint analysis of successive studies, median observation time differed greatly between the cohorts of the five defined time intervals.Since nearly all patients had been followed for at least 1 year and 93% of all documented first surgical interventions were performed within the first year following diagnosis, we focused on the intervention patterns within the first year.Delayed first interventions (beyond 365 days) spread up to 14 years after diagnosis and reflected very individual courses.

| Overall change of resection patterns over time
9][30][31] Gradually, realization of surgically induced late effects 4,9,10,17,32,33 and neurocognitive impairments after radiotherapy of tumor remnants, 34,35 as well as the advent of chemotherapy 7,12,15,26,27 started a process of rethinking of treatment approaches. 11,17,32,36,37In parallel, the understanding grew that monodisciplinary decisions should be substituted for a state-of-the-art multidisciplinary team (MDT) approach. 6,16,17,36,37nternational discussion questioned the benefit of radical surgical primarily for SML tumors, but resulting treatment recommendations were expanded to other sites.In our cohort, maximum tumor volume resection as first neurosurgical intervention dominated up to the year 2000, including a large fraction of subtotal resections.Starting from the early 2000s, the extent of first resection declined for SML LGG, while a marked reduction of the extent of resection occurred since the 2010s for tumors of the cerebral hemispheres and cerebellum.Over time, we observed more patients without any surgical intervention, more patients who had just an initial biopsy, and more patients with only partial resections.At the same time, the option to reach complete resection at second interventions became feasible, allowing to apply a safer strategy to preserve functional outcome in a low-grade tumor with long life expectancy. 11However, timing and frequency of repeated resections reflect the length of the observation time and cannot yet be judged in our cohort for the last years.Discussions on the general role of the neurosurgeon for SML tumors 9,30 acknowledged an often extensive involvement of critical structures precluding complete removal, especially in NF1-associated optic pathway gliomas (OPG).International consensus finally advocated not to attempt primary resection of chiasmatichypothalamic gliomas and tumors of comparable sites; rather, tumor-associated symptoms should be controlled by volume reduction, particularly if chemotherapy had failed or radiotherapy was not an option. 4,11,17,32his change in attitude was mirrored in our cohort by a significant early decline of volume-reducing resections, nearly abandoning complete/subtotal interventions during later time intervals in this subgroup of patients.Improved imaging allowed diagnosing more SML LGGs radiologically, a possible explanation for the early decline in the frequency of biopsies.8][39][40] Correspondingly, the number of biopsies rose in the mid-2010s, at the transition from TI4 to TI5.Over time, the portion of endoscopic biopsies increased over the stereotactic approach, though most interventions in the optic pathways remained open biopsies when tumors had no ventricular proximity or there was a risk for bleeding.Yet, it has clearly been reported that postoperative complication rates seem lower for stereotactic and endoscopic interventions compared to open biopsies. 10,32,41e trend for less invasive interventions as well as the growing quest for adequate biopsies to obtain molecular genetic information 37,42 were mirrored in the NF1-cohort as well.
Though surgery for SML-LGG should be delayed as long as possible, 17,32 our data indicate that most patients had their first intervention within the first 3 months.Still, SML-LGG represented more than half of all tumors with interventions >1 year after diagnosis; most were just biopsied.
While a larger percentage of patients had volumereducing surgery in the brainstem and spinal cord as compared to the SML, the extent of first resection declined at both sites. 43,44A widely constant portion of brainstem tumors were just resected partially, after dorsally exophytic tumors had even been judged "amenable for subtotal resection in the 1990s". 45As Histone3-K27M-mutated diffuse glioma WHO grade II had been found in these cohorts, 43 the portion of biopsies grew in later time intervals.Nearly all spinal tumors had histologic confirmation with less complete/subtotal and more partial resections over time.The necessity for multiple interventions has been reported, while the majority of spinal cord LGG can be treated successfully with surgery alone. 11,44hough the balance of radicality and post-surgical morbidity differs for the cerebral hemispheres and the cerebellum if compared to midline structures, 11 there are significant risks for long-term, post-surgical sequelae, e.g., the cerebellar mutism syndrome 46 or neurocognitive impairments. 33,47,48In the past, event-free survival remained higher for both sites following complete versus.7]11 Following the general recommendation for resection of amenable tumors at these sites, 5,11,16,49 >80% of all interventions in the cerebral hemispheres and >90% in the cerebellum concerned volume-reducing surgery in our cohort, with more extensive resections in the cerebellum at all times.Still, a significant shift was observed with a relative reduction of complete/subtotal resections and a parallel increase of partial resections.Especially, the portion of subtotal resections diminished in the cerebral hemispheres, having been a frequent surgical result in the 1990s. 29,50he additional impact of better radiological delineation of postoperative residues cannot be excluded. 21An intermittent increment of complete resections in the cerebellum and the temporal lobe in TI4 could be explained by backdated registration of patients treated "surgically only," 1 especially for patients receiving lesionectomy for epilepsy caused by ganglioglioma.T A B L E 3 (Continued) In total, interventions became less complete over time but not less frequent.Furthermore, almost 20% of our patients (with LGG of all sites) were in complete remission or stable disease at last follow-up despite having had incomplete initial surgery without subsequent treatment.The contribution of specific mutations to postsurgical growth impairment, cellular senescence, or any other mechanism is as yet unsettled. 51,52orresponding to the frequent association of posterior fossa lesions with symptoms of increased intracranial pressure, cerebellar LGG underwent surgery mostly "at diagnosis," while cerebral hemispheric LGG allowed for "more delayed" interventions.In parallel to less invasive procedures, such variable timing of interventions was most likely the result of detailed discussions in the MDTs.

| Impact of histology
Analyses concerning the extent of first resection in relation to tumor histology over time reflect the trend of less complete first interventions.Yet, the distribution of the extent of resection for histological subgroups parallels their distribution within CNS sites.Thus, tumor site rather than histology determined the extent of surgical intervention, though some histologies, for example diffuse glioma WHO grade II, may be less resectable at certain sites. 49Even if diagnostic imaging revealed details of tissue composition, no current recommendation relates histology to a specific surgical approach. 16

| Impact of age
For patients with first surgery within 1 year of diagnosis or 1 year of observation without surgery, median age was 5.89 years for SML LGG and 11.28 years for LGG of the cerebral hemispheres.Thus, the impact of age upon the extent of tumor resection seems to be mainly a consequence of the age-related shift in tumor location.The relative probability of complete resection increased with age, particularly as more LGG were located in the cerebral hemispheres and the cerebellum. 5,6In addition, only few adolescents remained observed without surgery within our cohort.Nevertheless, the decrease of the extent of surgery over time could be traced even in this age group, while it was most clearly discernable in the 5-9 and 10-15 year age groups.For infants and the age group 1-4 years at diagnosis, the decrease of the extent of resection with a parallel trend for more radiologic diagnoses could only be seen in early time intervals (TI1-3).During later intervals, their portion of histologically verified LGG increased by more biopsies and partial resections.

| Non-surgical therapy
15][16]26,27 Accordingly, the portion of patients receiving non-surgical therapy in our cohort corresponded inversely to the extent of surgical volume reduction at the various LGG sites.The advent of everolimus in later TIs reduced recruitment of TSC patients, in whom surgical intervention became rare but who account for a small number of patients only.Due to small numbers, the impact of prior non-surgical treatment upon surgery could not be judged.

| LIMITATIONS
Despite the large, population-based cohort, interpretation of our data and results is limited since German LGG studies focused on primary non-surgical treatment; all other aspects, including surgery, were prospectively documented, but with a restricted data set.
Assessment of neurocognitive development was recommended within all German cooperative multicenter brain tumor studies only since the 2010s, but sample size of pLGG patients remained small 33 precluding inclusion in the analysis of the extent of surgical resection over time.
Patient observation time relevantly differed between the three successive studies, limiting analysis to neurosurgical interventions during the first year following diagnosis.
Documentation of preoperatively defined surgical goals, intraoperative findings, and decisions during surgical intervention or of post-surgical change in neurological condition and its course was not common practice during the first LGG study.Due to limited resources, such routine documentation was not established throughout the subsequent years.
Unfortunately, we currently lack molecular-pathologic findings for the majority of tumors.The degree of infiltration and the probability of complete resection may be related to molecular subtypes.Molecular-histologic characterization has been integrated into current German brain tumor studies 2,53 allowing it to be considered for all relevant future study questions.

| CONCLUSIONS
Our results document a relevant change of the surgical resection pattern over time, whose most striking fact is a non-random, declining portion of complete/subtotal resections.This trend does not relate to changes in patients' characteristics or anatomical conditions.In contrast, it can be correlated to the evolution of comprehensive treatment algorithms that assign indications and limitations to all therapeutic modalities respecting age, tumor site and size, and NF1-status.Such seemingly less favorable results of the first surgical intervention may in fact be advantageous for longterm neurocognitive outcome and quality of life, at least in certain age groups or tumor locations, while they did not compromise long-term radiological outcome and survival.
The intended alignment to contemporary treatment algorithms conveys accepted surgical guidelines. 16The treatment plan must be discussed and agreed upon through the MDT before surgery occurs, including the reasons for surgery and the planned extent of resection tailored to the individual needs of each child.Surgery should be performed by a (pediatric) neurosurgeon with regular experience in the care of children with brain and spinal cord tumors and by techniques and approaches that minimize the risk of permanent postoperative deficits.Second-look surgery should be considered by the MDT if (recurrent or progressive) tumor residues that warrant treatment can be safely removed. 11lthough contemporary studies on pLGG continue to focus on (mostly targeted) non-surgical therapies for nonresected/non-resectable tumors, 25,[37][38][39] surgical aspects of the multimodal treatment strategy merit further investigation.Comprehensive documentation of the individual proceedings should include preoperative patient conditions, discussion and planning in the MDT (including the goal of surgery and possible second interventions), accurate surgical and anesthetic reports, and postoperative patient condition and course. 10Linking surgical documentation, post-surgical and medical/ophthalmologic morbidity, and long-term neurocognitive development might also allow to better delineate the respective roles for patient outcome and support further development of treatment algorithms. 33It is of key importance to understand how planning, performance, or tumor characteristics impact upon achieving surgical goals.

3. 2 . 6 |
Extent of resection by histology for first interventions within the first year (n = 3200)

F I G U R E 2
Extent of first resection for all and per tumor site.(A) Extent of first resection within the time intervals TI1-5; (B-F) Extent of first resection for interventions in the first year following diagnosis for tumor site per time interval TI1-5: B: cerebral hemispheres, C: supratentorial midline, D: cerebellum, E: caudal brainstem, F: spinal cord.

F I G U R E 3
Tumor site and extent of first resection for age.(A) Tumor location for age group at diagnosis; (B-F) Extent of first resection for interventions in the first year following diagnosis for age group at diagnosis per time interval TI1-5: B: <1 year, C: 1-4 years, D: 5-9 years, E: 10-15 years, F: ≥16 years.

T A B L E 1
Epidemiologic characteristics of the entire cohort (all patients: n = 4270) and of patients with at least 1 surgical intervention by time interval (TI) (n = 3440/4270).
(F) Spinal cord -resection 1st year per TI complete subtotal partial biopsy other no resection 1st year T A B L E 2

Change of resections patterns for tumor sites
Results of binary logistic regression analysis examining the extent of neurosurgical resection.
T A B L E 3 Ratio of selected variables in the final model.Odds calculated as P/ (1−P) with P = "Probability of the currently examined extent of resection."b p-Value of Wald test in final model/step of removal for selected/non- a Odds-